title: AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes.
abstract: The activation-induced cytidine deaminase (AID; also known as AICDA) enzyme is required for somatic hypermutation and class switch recombination at the immunoglobulin locus. In germinal-centre B cells, AID is highly expressed, and has an inherent mutator activity that helps generate antibody diversity. However, AID may also regulate gene expression epigenetically by directly deaminating 5-methylcytosine in concert with base-excision repair to exchange cytosine. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells. However, different studies have suggested either a requirement or a lack of function for AID in promoting pluripotency in somatic nuclei after fusion with embryonic stem cells. Here we tested directly whether AID regulates epigenetic memory by comparing the relative ability of cells lacking AID to reprogram from a differentiated murine cell type to an induced pluripotent stem cell. We show that Aid-null cells are transiently hyper-responsive to the reprogramming process. Although they initiate expression of pluripotency genes, they fail to stabilize in the pluripotent state. The genome of Aid-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably upregulated, including many MYC target genes. Recent studies identified a late step of reprogramming associated with methylation status, and implicated a secondary set of pluripotency network components. AID regulates this late step, removing epigenetic memory to stabilize the pluripotent state.
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Kumar
authors.forename: Lauren
authors.initials: L
authors.lastname: DiMenna
authors.forename: Nadine
authors.initials: N
authors.lastname: Schrode
authors.forename: Ting-Chun
authors.initials: TC
authors.lastname: Liu
authors.forename: Philipp
authors.initials: P
authors.lastname: Franck
authors.forename: Silvia
authors.initials: S
authors.lastname: Muñoz-Descalzo
authors.forename: Anna-Katerina
authors.initials: AK
authors.lastname: Hadjantonakis
authors.forename: Ali A
authors.initials: AA
authors.lastname: Zarrin
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chaudhuri
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.forename: Todd
authors.initials: T
authors.lastname: Evans
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D014157:Transcription Factors; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase